# Altered Dependencies of Melanoma on Rewired Post-Transcriptional Regulation

> **NIH NIH F30** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $50,520

## Abstract

PROJECT SUMMARY
The incidence of melanoma, the deadliest of all skin cancers, is rapidly increasing. Recent FDA-approved
targeted and immune therapies, the mainstay of treatment for metastatic melanoma, are constrained by
restricted efficacy, drug resistance, and severe toxicities. Thus, improved understanding of the mechanisms
driving melanoma progression remains an unmet medical need that could provide effective means of
preventing tumor recurrence with improved on-target therapeutic strategies.
Advances in next-generation sequencing technologies have uncovered widespread spicing aberrancies
across the majority of cancers. Although alternative splicing, predominantly regulated by RNA-binding
proteins (RBPs), serves to diversify more than 90% of human protein-coding genes, emerging studies
describe novel mechanisms by which this post-transcriptional regulation is hijacked to support oncogenic
programs. Recent efforts identify tumor-specific deregulation of the spliceosome complex and/or alternative
isoforms with oncogenic or tumor suppressive function. In melanoma, differential mRNA processing in
oncogenic drivers has been shown to promote metastasis and resistance to BRAF inhibition. Despite
compelling evidence that alternative splicing contributes to melanoma pathogenesis, a comprehensive study
of the molecular actors mediating this effect has not been performed. To address this, our lab profiled changes
in gene expression and histone marks in primary and metastatic melanoma patient samples, as well as control
melanocytes. Of 489 canonical RBPs, 17 RBPs in primary melanoma and 104 RBPs in metastatic melanoma
were significantly upregulated relative to healthy controls, with 52 RBPs were significantly upregulated in
metastatic sites relative to the primary site of disease.
To investigate dependencies on RBPs in melanoma pathogenesis, I have performed a CRISPR-Cas9
negative selection screening approach in human melanoma cell lines. As RBPs exert highly cell- and tissue-
specific function through RNA-binding domains (RBDs), single-guide(sg)RNAs were designed against the
RBDs of all 489 canonical RBPs. Using this negative-selection approach, I identified hnRNP A1 as an RBP
essential to melanoma in vitro. HnRNP A1, a ubiquitously expressed protein and member of the diverse family
of heterogeneous ribonucleoproteins, is broadly implicated in RNA processing events, such as splicing,
stability, nuclear export, and translation. HnRNP A1 expression was upregulated in melanoma relative to
melanocytes, and genetic ablation of hnRNP A1 revealed it to be critical to melanoma cell survival. The
proposed work will characterize the requirement for hnRNP A1 in melanoma. This work will elucidate the
complex post-transcriptional regulation underlying melanoma pathogenesis and provide a strong rationale for
developing novel therapeutic strategies, leveraging this information to improve patient outcomes.

## Key facts

- **NIH application ID:** 10062797
- **Project number:** 5F30CA232704-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Kathryn Grace Hockemeyer
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2019-09-30 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062797

## Citation

> US National Institutes of Health, RePORTER application 10062797, Altered Dependencies of Melanoma on Rewired Post-Transcriptional Regulation (5F30CA232704-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10062797. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*